Major cell-cell signaling pathways - Writ, Notch, Hedgehog {Hh), TGFb, receptor tyros=he kinase (RTK), nuclear receptor, Jak/STAT - control cell fate decisions during kidney development. However, very little is known about signaling systems other than TGFb and RTK in renal injury and chronic disease progression. Using a functional genomics approach, we demonstrated hierarchical interactions between TGFb and Notch or Writ pathways in mouse models of progressive renal disease and defined cell culture systems. These studies show that: 1) TGF-b acts upstream of the Notch pathway in epithelial-mesenchymal transdifferentiation (EMT), and Notch pathways genes Jagged1 (ligand), notch1 (receptor/signal transducer), hey1 (transcriptional target) are increased in kidneys of TGFb transgenics and CD2AP -/- mice with progressive glomerulosclerosis and interstitial fibrosis; 2) Expression of Dickkopf (secreted Wnt antagonists, induced) and Lrp (Wnt transmembrane coreceptors, repressed) family members is highly correlated with severity of glomerular and interstitial lesions; 3) Dickkopf 3 (dkk3) is a novel TGF-b-inducible Dkk family member of unknown function present in podocytes, but absent in mesangial, tubular and inflammatory cells. Together, these data suggest a working model by which TGF-b activates Notch signaling pathways, but inhibits Wnt signaling through activation of putative Writ antagonists Dkk3. Here we propose to test directly at a molecular level a putative, novel role for Dkk3 linking TGFb and Wnt signaling systems to promote apoptosis and EMT of renal cells as fundamental pathomechanisms underlying renal disease progression. The Specific Aims are to: 1. Characterize at signaling systems level Dkk, Wnt and TGF signaling components in kidney in vitro and in vivo. 2. Examine autocrine and paracrine function and activities of Dkk3 expression in single and coculture of routine gtomerular cells. 3. Identify and validate Dkk3 binding proteins and/or receptors in glomeruiar cells. This work will examine at molecular detail a novel model of signaling systems interaction between TGFb and Dkk/Wnt pathways and validate for the first time its relevance to glomerular cell biology and progression of renal disease in murine models.